The treatment of cancer typically requires the optimal sequence of one or more of the effective treatments (e.g. surgery, radiotherapy, and chemotherapy). Patients for whom the disease is at an early stage can frequently be operated on to remove the cancer. In many cancers follow up adjuvant chemotherapy is required for micro-metastatic disease. In others with locally advanced or metastatic disease, cancer control relies on radiotherapy and/or chemotherapy. In cancer therapy, failure to cure the disease generally results from intrinsic or acquired tumour cell resistance to drugs or radiotherapy. In such instances, the treatments become ineffective and survival times for such patients may be considerably reduced. Thus it is important to develop new approaches to cancer which may enhance the cytotoxicity of known chemotherapeutic agents.
The combination of external radiation and chemotherapy has in many instances been reported to have a synergistic effect on therapy. However, combining these two modalities effectively relies on an unending of the mechanisms that lead to the enhanced therapeutic index and the exploitable differences in the properties of tumours and normal tissues.
Platinum based chemotherapeutic agents are used in the treatment of cancers. These agents exert their cytotoxic effect by binding with the DNA of the cancer cell and causing strand breaks, and consequently preventing the cell from dividing further and causing cell death. A number of mechanisms are manifested in in vitro resistance to the chemotherapeutic agents. They are usually manifested in decreased transport of the drug into the cell, thiol inactivation, enhanced DNA repair or a combination of some or all of these mechanisms. There is a need for an effective method to monitor the development of resistance to platinum based chemotherapeutic agents in vivo, and for an effective method for assessing the effectiveness of treatment of diseases such as cancer which are undergoing treatment by administration of a platinum based chemotherapeutic agent.
Cisplatin (cis-dichlorodiammine-platinum(II)) and carboplatin (cis-diammine(1,1-cyclobutanedicarboxylato) platinum(II)) are the two most widely prescribed platinum based chemotherapeutic agents at the present time. Reports have appeared in the literature of the use of radiolabelled cisplatin to assess the biodistribution of cisplatin in animals. However, to date there has been no medical use of radiolabelled platinum based therapeutic agents. The methods whereby radiolabelled cisplatin has hitherto been prepared suffer from a number of disadvantages. They use as their starting point platinum metal which has been enriched in a radioisotope of platinum by irradiation of platinum metal in a nuclear reactor, typically with neutrons.
Starting with platinum metal, the synthesis of radiolabelled cisplatin is relatively time consuming requiring in the order of 6.5 hours to complete. For radionuclides with half-lives of hours, a few hours' delay in the preparation of radiolabelled cisplatin can lead to significant loss of specific activity, especially as in a production environment this amount of delay may result in product only reaching a patient on the following working day. Such a delay causes significant loss of specific activity of the radioisotope. In this instance, in order for a desired amount of radioactivity to be administered to a patient, the overall dosage of unradiolabelled cisplatin carrier will be increased as the specific activity of the radiolabelled substance decreases. It may then become impractical to administer sufficient of the agent to deliver the desired amount of radioactivity if the specific activity is too low.
By contrast, a significantly shorter synthesis time can permit the distribution of the product and its administration to the patient on the same day as the agent is administered, without the concomitant loss in specific activity.
Furthermore the prior art synthesis of cisplatin from platinum metal exhibits relatively low and variable yields, and is unreliable and may at times give no yield of the desired product. Low yield of radiolabelled cisplatin or other radiolabelled chemotherapeutic agents starting with radiolabelled platinum metal (which is expensive) results in a high cost of the radiolabelled chemotherapeutic agent and the possibility of insufficient dose being available for treatment of a patient. Similarly, unreliability of prior art synthetic methods and the occurrence of failures is totally unsatisfactory in a clinical context.
Still further, the “hot cell” facilities required for die synthesis of a radiolabelled chemotherapeutic such as cisplatin are expensive and there are significant economic benefits to be gained from a shortened synthesis, permitting greater throughput in the hot cell.
There is therefore a need for a shortened and more reliable method of synthesis of radiolabelled platinum based chemotherapeutic agents.
The present invention seeks to provide methods of synthesis of radiolabelled platinum based chemotherapeutic agents which provide a decrease in the synthesis time compared to previously known methods, and improved, more reliable yields, thereby allowing greater scope diagnostic, therapeutic and related applications.
The present invention also seeks to provide methods of incorporation of radionuclides such as 195mPt with both an imageable and a therapeutic emission into platinum based chemotherapeutic agents to facilitate use of the resultant radiolabelled agent (a) to determine the appropriate dosage of the chemotherapeutic agent in a patient, and/or (b) to determine the effectiveness of the chemotherapeutic agent in a patient, and/or (c) as a monitor of drug resistance and/or (d) to enhance cytotoxic effects by exploiting synergistic cytotoxic drug-radiation interactions.